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Lipid storage disorders (or lipidoses) are a group of inherited metabolic disorders in which harmful amounts of lipids accumulate in some of the body's cells and tissues. People with these disorders generally either do not produce enough of one of the enzymes needed to metabolize lipids or they produce enzymes that do not work properly. Over time, this excessive storage of fats can cause permanent cellular and tissue damage.
Many lipid storage disorders lack adequate therapeutics for treatment. These disorders include, for example, Niemann-Pick disease types A, B and C, Gaucher disease Type II, Fabry disease (note that an enzyme replacement is available), gangliosidoses including Tay-Sachs disease, Sandhoff disease, Krabbe disease, Metachromatic leukodystrophy, and cholesteryl ester storage disease (Wolman's disease).
Niemann-Pick disease is an inherited autosomal recessive lipid storage disorder characterized by excessive accumulation of sphingomyelin in the lysosomes of cells such as macrophages and neurons, which impairs normal cellular function. Niemann-Pick Type A results from a deficiency of acid sphingomyelinase and is a rapidly progressive neurodegenerative disease. It typically results in death within two to three years of age. Niemann-Pick Type B is a milder form that results in the enlargement of the liver and spleen, and respiratory distress with death generally ensuing by early adulthood. These two forms of Niemann-Pick disease which are both associated with acid sphingomyelinase (ASM) deficiencies are referred to collectively herein as Niemann-Pick disease, or ASM deficiency (ASMD). Other types of Niemann-Pick disease, e.g., Type C, do not involve mutations in the ASM gene and are not directly attributable to the function of ASM. The nature of the biochemical and molecular defects that underlie the remarkable clinical heterogeneity of the A and B subtypes remains unknown. Although patients with both subtypes have residual ASM activity (about 1 to 10% of normal), biochemical analysis cannot reliably distinguish the two phenotypes. Moreover, the clinical course of Type B NPD is highly variable, and it is not presently possible to correlate disease severity with the level of residual ASM activity.
Niemann-Pick Type C is results from mutations in NPC1 and NPC2 genes. In Niemann-Pick Type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene has been shown to be a small cholesterol-binding protein that resides in the lysosome lumen. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.
Niemann Pick disease, as well as other lipid storage disorders, is a disorder for which there remains an overwhelming need for therapeutics for treatment. Presently there is no FDA approved therapy for Neimann Pick disease in the United States; and treatments for this disease are limited with most people afflicted with Type A dying by age 18 months, while those with Type B or Type C, frequently live into their teenage years.